Highly efficient synthesis of thieno[2,3-b]indole derivatives

Article abstract of DOI:10.1002/hlca.200800423

Thieno[2,3-b]indole derivatives were efficiently prepared via the reaction of 1,3-dihydro-2H-indole-2-thiones with α-bromo-substituted ketones or aldehydes and in the presence of Et₃N (Scheme 2 and Table). The reaction took place under very mil

Full text of DOI:10.1002/hlca.200800423

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Helvetica Chimica Acta – Vol. 92 (2009)
Highly Efficient Synthesis of Thieno[2,3-b]indole Derivatives
by Hassan Zali Boeini*
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, Iran
(phone: þ 98-311-7932715; fax: þ 98-311-6689732; e-mail: h.zali@chem.ui.ac.ir)
Thieno[2,3-b]indole derivatives were efficiently prepared via the reaction of 1,3-dihydro-2H-indole-
2-thiones with a-bromo-substituted ketones or aldehydes and in the presence of Et3N (Scheme 2 and
Table). The reaction took place under very mild conditions and in short times with good to excellent
yields.
Introduction. – Thienoindole derivatives are important target compounds because
they have potential biological activities with applications in agricultural chemistry and
pharmaceutical industries. So design and synthesis of thienoindoles have attracted
more and more attention over the years. For instance, thienodolin (¼6-chloro-8H-
thieno[2,3-b]indole-2-carboxamide), which was extracted from the fermentation
mixture of a streptomycete strain, specified as Streptomyces albogriseolus, has shown
both growth-promoting and -inhibiting activities in rice seedlings [1]. Thienoindoles are
also widely used in medicinal chemistry with applications in drug discovery and
development [2], and in organic electronics as novel electroluminescence materials for
designing light-emitting devices [3]. Therefore, development of an efficient procedure
for the synthesis of substituted thienoindoles is still an urgent need.
Results and Discussion. – One approach to thienoindole derivatives benefits from
triflic anhydride ((CF3SO2)2O) promoted cyclization of sulfides [4]. This route is
restricted to the synthesis of dihydro thienoindole derivatives. The most convenient
method for preparing thienoindoles is the reaction of oxindole derivatives having a
C¼O group in position 3 with P4S10 in a suitable solvent [5]. Although this reaction
takes place with fair to good yields, some drawbacks are associated with the method,
which are a long reaction time (several hours) and the sluggishness of the trans-
formation. Recently, a Pauson – Khand-type reaction of 2-(alkynyl)phenyl isothiocya-
nates with stoichiometric amounts of [Co2(CO)8] has been developed for the synthesis
of 2H-thieno[2,3-b]indol-2-ones [6].
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
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Thioamides have been used as useful synthons in the synthesis of heterocycles [7].
Others and we have shown the versatility of these compounds for the synthesis of S-
containing heterocycles [8]. For example, thioacetomorpholides (¼1-(morpholin-4-
yl)ethanethione) have been successfully used for the construction of fully substituted
thiophenes. In continuation of our work on the synthesis of S-heterocycles from
thioamides, we now report a rapid, versatile, and mild method for the preparation of
substituted thienoindoles via the reaction of 1,3-dihydro-2H-indole-2-thiones 1 with a-
bromo-substituted ketones or aldehydes 21) in the presence of Et3N.
The starting 1,3-dihydro-2H-indole-2-thiones 1 could easily be prepared by reaction
of the corresponding 1,3-dihydro-2H-indol-2-ones with P4S10 (or Lawesson reagent) in
a suitable solvent (Scheme 1).
Scheme 1a)
Then, a 1,3-dihydro-2H-indole-2-thione 1 was treated with an equimolar amount of
a suitable a-bromo-substituted ketone or aldehyde 2 at room temperature in the
presence of Et3N in DMFas solvent to obtain the thienoindole 3 within a short time and
in good to excellent yield (Scheme 2 and Table).
Thus, a wide variety of substituted thienoindoles were obtained by this method; e.g.,
2,5-dimethyl-8H-thieno[2,3-b]indole (3g) was isolated from the reaction of 2-
bromopropanal and 1,3-dihydro-5-methyl-2H-indole-2-thione in very good yield
(88%) after only 15 min.
Other types of heterocyclic thioamides could also be subjected to the described
procedure. Thus, when 1H-benzimidazole-2-thiol was treated with chloroacetone for
3 h, compound 3h could easily be isolated by pouring the reaction mixture in aqueous
MeOH (Scheme 3).
Scheme 2a)
1
)
The reaction also works properly with a-chloro-substituted ketones or aldehydes.

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Helvetica Chimica Acta – Vol. 92 (2009)
Table. One-step Synthesis of Thieno[2,3-b]indoles
Thioamide 1
Ketone or aldehyde 2
Time [min]
Product 3a)
Yield [%]b)
85
R
H
R1
R2
R3
H
Me
H
15
3a
Cl
Me
H
H
Me
Me
Me
Me
H
H
H
H
20
20
15
25
3b
3c
3d
3e
93
80
87
78
H
Me
Ph
H
H
Me
H
H
H
Me
Me
15
15
3f
3g
83
88
Me
a
) All compounds were characterized with H- and 13C-NMR, IR, and elemental analysis. b) The yields
1
refer to isolated pure compounds.

Helvetica Chimica Acta – Vol. 92 (2009)
1271
Scheme 3
A mechanism is proposed for the reaction course (Scheme 4). The cyclic thioamide
undergoes first an S-alkylation with the a-halocarbonyl compound, and the subsequent
treatment with the base leads to ring closure to the thienoindole by elimination of H2O.
Scheme 4
Conclusions. – A new, general, efficient, and simple procedure for the preparation
of substituted thieno[2,3-b]indoles was developed. The reaction proceeds under very
mild conditions and within a rather short time. The isolation of the products is also very
simple. Moreover, the starting materials are cheap and readily available. The new
materials (and their variants) have potential to be used as antiviral drugs and in
agricultural chemistry.
Providing of facilities for this work from the University of Isfahan is gratefully acknowledged.
Experimental Part
General. All solvents used were dried and distilled before use according to standard procedures.
M.p.: in sealed capillaries; uncorrected. Anal. TLC: silica gel (SiO2; Merck 60 F254) coated on aluminium
plates; visualizing by UV and by aq. KMnO4 soln. IR Spectra: UR-20 spectrometer; KBr pellets; ˜n in
cmꢀ1. 1H-NMR Spectra: Bruker AMX-500 spectrometer; CDCl3 solns; d in ppm rel. to Me4Si as internal
standard, J in Hz.
1,3-Dihydro-2H-indole-2-thiones 1: General Procedure. A soln. of 1,3-dihydro-2H-indol-2-ones
(10 mmol) in dry THF (20 ml) and P2S5 (11 mmol, 2.44 g) were stirred at 458 for 1 – 2 h. Then, the mixture
was filtered, the filtrate treated with 5% aq. NaHCO3 soln. (20 ml) and extracted with AcOEt (30 ml),
the extract concentrated, and the residue purified by flash column chromatography (SiO2, AcOEt/
hexane 1:4) to give the cyclic thioamides as light yellow solids.
Compounds 3a – 3g: General Procedure. The 1,3-dihydro-2H-indole-2-thione (2 mmol) and the a-
bromo-substituted carbonyl compound (2.2 mmol) were dissolved in DMF (2 ml) at r.t. and stirred for
the times noted in the Table. At the end of reaction, Et3N (2.5 mmol, 0.35 ml) was added and the mixture
stirred and poured in MeOH/H2O 80 :20 (20 ml). The precipitated compound was filtered and
recrystallized in a suitable solvent to afford the target compounds as colorless solids.
3-Methyl-8H-thieno[2,3-b]indole (3a): IR: 3392, 2916, 2493, 2123, 1647, 1613. 1H-NMR: 8.18 (s, 1 H);
7.88 (d, J ¼ 7.6, 1 H); 7.42 (d, J ¼ 7.9, 1 H); 7.20 – 7.27 (m, 2 H); 6.49 (s, 1 H); 2.66 (s, 3 H). 13C-NMR:

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Helvetica Chimica Acta – Vol. 92 (2009)
142.5; 141.2; 129.9; 125.7; 123.3; 122.3; 120.2; 119.1; 112.7; 111.6; 15.5. Anal. calc. for C11H9NS (187.26): C
70.55, H 4.84, N 7.48; found: C 70.86, H 4.71, N 7.40.
1
5-Chloro-3-methyl-8H-thieno[2,3-b]indole (3b): IR: 3390, 2910, 2499, 2120, 1648, 1615. H-NMR:
7.98 (d, J ¼ 1.3, 1 H); 7.33 (dd, J ¼ 8.6, 1.8, 1 H); 6.80 (d, J ¼ 8.6, 1 H); 6.46 (s, 1 H); 2.24 (s, 1 H).
13C-NMR: 142.4; 140.5; 129.7; 125.8; 124.9; 123.9; 122.3; 118.6; 112.3; 15.2. Anal. calc. for C11H8ClNS
(221.71): C 59.59, H 3.64, Cl 15.99, N 6.32; found: C 60.11, H 3.50, Cl 15.75, N 6.36.
3,5-Dimethyl-8H-thieno[2,3-b]indole (3c): IR: 3399, 2920, 2501, 2129, 1652, 1621. 1H-NMR: 7.49 (m,
1 H); 7.06 (m, 2 H); 6.47 (s, 1 H); 5.61 (s, 1 H); 2.57 (s, 3 H); 2.20 (s, 3 H). 13C-NMR: 142.6; 142.0; 129.8;
125.1; 123.2; 122.6; 121.9; 112.9; 112.7; 109.4; 23.6; 19.2. Anal. calc. for C12H11NS (201.29): C 71.60, H 5.51,
N 6.96; found: C 71.81, H 5.46, N 7.05.
3,8-Dimethyl-8H-thieno[2,3-b]indole (3d): IR: 3387, 2911, 2496, 2125, 1645, 1612. 1H-NMR: 7.62 (d,
J ¼ 7.8, 1 H); 7.35 – 7.37 (m, 2 H); 7.15 (t, J ¼ 7.1, 1 H); 6.84 (s, 1 H); 3.92 (s, 3 H); 1.97 (s, 3 H). Anal. calc.
for C12H11NS (201.29): C 71.60, H 5.51, N 6.96; found: C 72.0, H 5.43, N 6.81.
3-Methyl-8-phenyl-8H-thieno[2,3-b]indole (3e): IR: 3385, 2918, 2489, 2127, 1641, 1613. 1H-NMR:
7.58 – 7.62 (m, 3 H); 7.48 – 7.54 (m, 3 H); 7.15 – 7.19 (m, 3 H); 6.83 (s, 1 H); 2.17 (s, 3 H). Anal. calc. for
C17H13NS (263.36): C 77.53, H 4.98, N 5.32; found: C 77.70, H 5.22, N 5.50.
2,8-Dimethyl-8H-thieno[2,3-b]indole (3f): IR: 3391, 2910, 2492, 2128, 1646, 1616. 1H-NMR: 7.71 (d,
J ¼ 7.9, 1 H); 7.33 (d, J ¼ 8.7, 1 H); 7.25 (t, J ¼ 7.9, 1 H); 7.14 (t, J ¼ 7.7, 1 H); 7.04 (s, 1 H); 3.92 (s, 3 H); 2.65
(s, 3 H). Anal. calc. for C12H11NS (201.29): C 71.60, H 5.51, N 6.96; found: C 71.81, H 5.39, N 6.91.
2,5-Dimethyl-8H-thieno[2,3-b]indole (3g): IR: 3398, 2913, 2489, 2123, 1641, 1615. 1H-NMR: 8.17 (s,
1 H); 7.22 (d, J ¼ 7.9, 1 H); 7.15 (d, J ¼ 7.9, 1 H); 6.99 (s, 1 H); 6.51 (s, 1 H); 2.90 (s, 3 H); 2.73 (s, 3 H).
Anal. calc. for C12H11NS (201.29): C 71.60, H 5.51, N 6.96; found: C 71.66, H 5.35, N 7.12.
1
3-Methylthiazolo[3,2-a]benzimidazole (3h): IR: 3410, 2970, 2539, 2162, 1655, 1625. H-NMR: 7.81
(d, J ¼ 7.9, 1 H); 7.79 (d, J ¼ 7.9, 1 H); 7.37 (t, J ¼ 7.6, 1 H); 7.25 (t, J ¼ 7.7, 1 H); 6.35 (s, 1 H); 2.75 (s, 3 H).
13C-NMR: 157.2; 149.8; 131.1; 129.7; 123.4; 120.5; 120.1; 110.8; 104.1; 13.7. Anal. calc. for C10H8N2S
(196.31): C 63.80, H 4.28, N 14.88; found: C 64.01, H 4.21, N 14.75.
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Received November 24, 2008